Well-differentiated tumors (papillary and follicular thyroid cancer) are highly treatable and usually curable. Poorly differentiated and undifferentiated thyroid tumors (anaplastic thyroid cancer) are less common, aggressive, metastasize early, and have a poorer prognosis. Medullary thyroid cancer is a neuroendocrine cancer that has an intermediate prognosis.

The
thyroid gland may occasionally be the site of other primary tumors, including
sarcomas, lymphomas, epidermoid carcinomas, and teratomas. The thyroid may also be the site
of metastasis from other cancers, particularly of the lung, breast, and kidney.

Incidence and Mortality

Estimated new cases and deaths from thyroid cancer in the United States in 2018:
[2]

New cases: 53,990.

Deaths: 2,060.

Thyroid
cancer affects women more often than men and usually occurs in
people aged 25 to 65 years. The incidence of this malignancy has
been increasing over the last decade. Thyroid cancer commonly presents
as a so-called cold nodule. It is detected as a palpable thyroid gland during a physical exam and evaluated with iodine 131I scans; scintigraphy shows that the isotope is not taken up in an area of the gland. The overall incidence of cancer in a cold nodule is 12% to
15%, but it is higher in people younger than 40 years and in people with calcifications present on preoperative ultrasonography.
[3]
[4]

Anatomy

Thyroid gland tissue envelops the upper trachea just below the thyroid and cricoid cartilages that make up the larynx. The gland has an isthmus and often asymmetric right and left lobes; usually four parathyroid glands lie posteriorly. When swallowing, the thyroid may be felt to rise with the larynx—most commonly in the presence of a disease process.

Anatomy of the thyroid and parathyroid glands.

Risk Factors

Patients with a history of radiation therapy administered in infancy or childhood for
benign conditions of the head and neck (such as
enlarged thymus, tonsils, or adenoids; or acne) have an increased risk of cancer and
other abnormalities of the thyroid gland. In this group of patients,
malignancies of the thyroid gland appear as early as 5 years
after radiation therapy and may appear 20 or more years later.
[5]
Radiation exposure as a consequence of nuclear fallout has also been associated with a high risk of thyroid cancer, especially in children.
[6]
[7]
[8]

Diagnostic and Staging Evaluation

The following tests and procedures may be used in the diagnosis and staging of thyroid cancer:

Physical exam and history.

Laryngoscopy.

Blood hormone studies.

Blood chemistry studies.

Ultrasound exam.

Computed tomography scan.

Fine-needle aspiration biopsy of the thyroid.

Surgical excision.

Prognostic Factors for Well-differentiated Thyroid Cancer

Age appears to be the
single most important prognostic factor.
[12]
The prognosis for differentiated
carcinoma (papillary or follicular) without
extracapsular extension or vascular invasion is better for patients younger than 40 years.
[12]
[13]
[14]
[15]
[16]

Patients considered at low risk according to age, metastases, extent, and size risk criteria include women younger than 50 years and men younger
than 40 years without evidence of distant metastases. The low-risk group also includes older patients with primary papillary tumors smaller than 5
cm without evidence of gross extrathyroid
invasion, and older patients with follicular cancer without major capsular invasion or blood
vessel invasion.
[14]
Using these criteria, a retrospective study of 1,019
patients showed that the 20-year survival rate was 98% for low-risk patients and
50% for high-risk patients.
[14]

A
retrospective surgical series of 931 previously untreated patients with
differentiated thyroid cancer found that age older than 45 years, follicular histology, primary tumor larger than 4
cm (T2–T3), extrathyroid extension (T4), and distant metastases were adverse prognostic factors.
[17]
[18]
Favorable prognostic factors included female gender, multifocality, and
regional lymph node involvement.
[17]
Other studies, however, have shown that regional lymph node involvement had no
effect
[19]
[20]
or had an adverse effect on survival.
[15]
[16]
[21]

Another retrospective series of 1,807 patients found that the presence of distant metastases was most predictive of survival, followed by age.
[22]
An age cutoff of 55 years was identified as most predictive of survival. This led to an international multi-institutional validation of age 55 years as a cutoff for risk stratification in the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system for well-differentiated thyroid cancer. This analysis of 9,484 patients was responsible for the change in age cutoff from 45 years to 55 years in the AJCC Cancer Staging Manual, 8th edition, using AJCC/UICC staging for well-differentiated thyroid cancer.
[23]

The prognostic significance of lymph node status is controversial. Use of sentinel lymph node biopsy may aid in identifying patients with occult metastases who might benefit from central neck dissection.
[24]

Diffuse, intense
immunostaining for vascular endothelial growth factor in patients with
papillary cancer has been associated with a high rate of local recurrence and
distant metastases.
[25]
An elevated serum thyroglobulin level correlates
strongly with recurrent tumor when found in patients with differentiated
thyroid cancer during postoperative evaluations.
[26]
[27]
Serum thyroglobulin
levels are most sensitive when patients are hypothyroid and have elevated serum
thyroid-stimulating hormone levels.
[28]
Expression of the tumor suppressor
gene p53 has also been associated with an adverse prognosis for patients with
thyroid cancer.
[29]

Nixon IJ, Wang LY, Migliacci JC, et al.: An International Multi-Institutional Validation of Age 55 Years as a Cutoff for Risk Stratification in the AJCC/UICC Staging System for Well-Differentiated Thyroid Cancer. Thyroid 26 (3): 373-80, 2016.[PUBMED Abstract]

Cellular Classification of Thyroid Cancer

In thyroid cancer, cell type is an important determinant of prognosis and treatment. The thyroid has two cell types: follicular cells and parafollicular C cells. The management of thyroid cancer depends on the cell of origin and how well the integrity of the cell type is maintained. The four main types of thyroid cancer are divided into the following two categories for clinical management:
[1]

Stage Information for Thyroid Cancer

Definitions of TNM

The American Joint Committee on Cancer has designated staging by the TNM (tumor, node, and metastasis)
classification to define thyroid cancer.
[1]
[2]
Definitions of TNM stages for each type of thyroid cancer are described in the following sections of this summary:

Papillary and Follicular Thyroid Cancer

Clinical Features and Prognosis

The clinical features and prognosis of well-differentiated thyroid tumors vary by stage.

Most papillary cancers have some follicular elements. These follicular elements may outnumber the papillary formations, but they do not
change the prognosis.

Follicular adenomas, which are characterized by their lack of invasion through
the capsule into the surrounding thyroid tissue, must be distinguished from follicular thyroid carcinoma. While follicular cancer has a good prognosis, it
is less favorable than that of papillary carcinoma. The 10-year survival is better for
patients with follicular carcinoma without vascular invasion than it is for
patients with vascular invasion.

Papillary carcinomas metastasize more frequently to regional lymph nodes than
to distant sites. Follicular carcinomas more commonly invade blood vessels and metastasize hematogenously to the lungs and to the bone rather than through the
lymphatic system. When metastases occur, treatment with radioiodine is initially effective, but prognosis worsens as resistance to radioiodine ensues.

Staging and prognosis of papillary and follicular thyroid cancer are determined by the age and site of the disease. The clinical features and prognoses for papillary thyroid cancer include the following:

Stage I papillary or follicular thyroid cancer

is localized to the thyroid gland in patients aged 55 years or older. In those younger than 55 years, the cancer may have spread to nearby tissues and lymph nodes but not to other parts of the body. In as many as 50% of the cases, papillary thyroid cancer is multifocal.

Stage II papillary or follicular thyroid cancer

is defined by either of the following descriptions: (1) patients are younger than 55 years and the tumor has spread from the thyroid to distant parts of the body, or (2) patients are aged 55 years or older: and the tumor is confined to or has limited invasion outside of the thyroid, with or without lymph node involvement, but without spread to distant parts of the body. Stage II is the most advanced stage possible in a patient younger than 55 years.

Stage III papillary or follicular thyroid cancer

is only possible in patients aged 55 years or older. The thyroid tumor demonstrates extension into surrounding soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. There may or may not be lymph node involvement, but there is no distant spread to other parts of the body.

Stage IVa papillary or follicular thyroid cancer

is only applicable for patients aged 55 years or older. The thyroid tumor demonstrates extension into surrounding soft tissues that includes either prevertebral fascia or encases the carotid artery or mediastinal vessels. There may or may not be lymph node involvement, but there is no distant spread to other parts of the body.

Stage IVb papillary or follicular thyroid cancer

is only applicable for patients aged 55 years or older. It is defined by the presence of distant spread to other parts of the body. The lungs and bones are the most frequent sites of distant spread.

Hürthle cell carcinoma is a variant of follicular carcinoma with a similar prognosis and is treated in the same way as equivalent stage non-Hürthle cell follicular carcinoma.
[1]

Localized/regional papillary and follicular thyroid cancer

Surgery is the therapy of choice for all primary lesions. Surgical options
include total thyroidectomy or lobectomy. The choice of procedure is
influenced mainly by the age of the patient and the size of the nodule.
Survival results with the two procedures are similar for early-stage disease, with differences in the rates
of surgical complications and local recurrences.
[2]
[3]
[4]
[5]
[6]
[7]
[8]

Surgery

The objective of surgery is to completely remove the primary tumor, while minimizing treatment-related morbidity, and to guide postoperative treatment with RAI. The goal of RAI is to ablate the remnant thyroid tissue to improve the specificity of thyroglobulin assays, which allows the detection of persistent disease by follow-up whole-body scanning. For patients undergoing RAI, removal of all normal thyroid tissue is an important surgical objective. Additionally, for accurate long-term surveillance, RAI whole-body scanning and measurement of serum thyroglobulin are affected by residual, normal thyroid tissue, and in these situations, near total or total thyroidectomy is required. This approach facilitates follow-up thyroid scanning.

Total thyroidectomy

Total thyroidectomy is often used because of the high
incidence of multicentric involvement of both lobes of the gland and the
possibility of dedifferentiation of any residual tumor to the anaplastic cell
type.

For a papillary thyroid cancer tumor that measured less than 1 cm, the extent of surgery did not impact recurrence (P = .24) or survival (P = .83).

For tumors that measured 1 cm or larger, lobectomy resulted in higher risk of recurrence (P = .04) and death (P = .009).

To minimize the influence of larger tumors, 1-cm to 2-cm lesions were examined separately. Lobectomy resulted in a higher risk of recurrence (P = .04) and death (P = .04).

Total thyroidectomy resulted in lower recurrence rates and improved survival for patients with papillary thyroid cancer tumors that measured 1 cm or larger compared with lobectomy.

In a pattern-of-care study that used the NCDB registry from 1985 to 2003, 57,243 papillary thyroid cancer patients with tumors measuring 1 cm or larger underwent total thyroidectomy or lobectomy. Trends in the extent of surgery were examined for patients with papillary thyroid cancer over two decades. Logistic regression was used to identify factors that predict the use of total thyroidectomy compared with lobectomy.
[10]
[Level of evidence: 3i]

Use of total thyroidectomy increased from 70.8% in 1985 to 90.4% in 2003 (P < .0001).

Patients treated at high-volume medical facilities or academic centers were more likely to undergo total thyroidectomy than were patients examined at low-volume medical facilities or community hospitals (P < .0001).

Lobectomy

Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of previous head and neck irradiation or radiologically or clinically involved cervical nodal metastases. This procedure is associated with a lower incidence of
complications, but approximately 5% to 10% of patients will have a recurrence
in the thyroid after a lobectomy.
[11]

Abnormal regional lymph nodes are biopsied at the time of
surgery. Recognized involved nodes are removed at initial surgery, but
selective node removal can be performed, and radical neck dissection is usually not
required.
This
results in a decreased recurrence rate but has not been shown to improve
survival.
Follicular thyroid cancer commonly metastasizes to lungs and bone. When a remnant lobe remains, use of 131I as ablative therapy is compromised because the radioiodine will be preferentially taken up by the remnant normal tissue rather than by the tumor.

Radioactive iodine (RAI) therapy

Studies have shown that a postoperative course of therapeutic
(ablative) doses of radioiodine 131I results in a decreased recurrence rate among high-risk patients with papillary
and follicular carcinomas.
[5]
RAI may be given in addition to exogenous thyroid
hormone but is not considered routine.
[12]
RAI treatment is optimal after total thyroidectomy with minimal thyroid remnant. With a large thyroid remnant, a low thyroglobulin level cannot be achieved, which increases the chance of requiring multiple doses of RAI.

Consideration of RAI for remnant ablation is based on pathological risk features including the following:

The size of the primary tumor.

The presence of lymphovascular invasion.

Capsule invasion.

The number of involved lymph nodes.

RAI may be given with one of two methods of thyroid-stimulating hormone (TSH/thyrotropin) stimulation:

Withdrawal of thyroid hormone.

Administration of recombinant human thyrotropin (rhTSH).

Administered rhTSH maintains quality of life and reduces the radiation dose delivered to the body compared with thyroid hormone withdrawal.
[13]
Patients presenting with papillary
thyroid microcarcinomas (tumors <10 mm), which are considered to be very low risk, have an excellent prognosis when
treated surgically. Additional therapy with 131I would not be expected to
improve the prognosis.
[14]

The role of RAI in low-risk patients is not clear because disease-free survival (DFS) or overall survival (OS) benefits have not been demonstrated.

Evidence (surgery with or without RAI):

One study reviewed 1,298 low-risk patients from the French Thyroid Cancer Registry.
[15]
Patients were identified as having low-risk papillary or follicular cancer as they are defined by the American Thyroid Association and the European Thyroid Association criteria, which include the following:

Complete tumor resection.

Multifocal tumors 1 cm or smaller confined to the thyroid.

Tumors larger than 1 cm but no larger than 4 cm confined to the thyroid.

No lymph node involvement or distant metastatic disease.

Of the 1,298 patients, 911 patients received RAI after surgery, and 387 patients did not receive RAI after surgery. The follow-up period was 10.3 years.

In multivariate analyses, there were no differences in OS (P = .243) or DFS (P = .2659), according to RAI use.
[15]

Long-term complications of RAI using 131I include the following:

Second malignancies.

Sialadenitis.

Lacrimal and salivary gland dysfunction.

Options for reducing the amount of radiation exposure by reducing the amount of RAI in each dose and also giving RAI in combination with rhTSH injections have been explored for low-risk thyroid cancer patients.

Evidence (thyroid hormone withdrawal or use of rhTSH with 131I):

A phase III, randomized, noninferiority study of patients with low-risk thyroid cancer using a comparison of two thyrotropin-stimulation methods (thyroid hormone withdrawal or use of rhTSH) and two doses of 131I (1.1GBq [30mCi] and 3.7GBq [100mCi]) using a 2 × 2 factorial design was reviewed.
[16]
[Level of evidence: 3iA]

Equivalent thyroid ablation rates between high- and low-dose 131I at 6 to 10 months after administration of 131I were recorded.

Patients with more advanced T stage (T1–T3, N0–1) and with less than a total thyroidectomy were included with a lower overall ablation rate of 85%.

Another phase III, randomized, noninferiority study of patients with low-risk thyroid cancer using a comparison of two thyrotropin-stimulation methods (thyroid hormone withdrawal or use of rhTSH) and two doses of 131I (1.1GBq [30mCi] and 3.7GBq [100mCi]) using a 2 × 2 factorial design was reviewed. The inclusion criteria consisted of a low-risk, homogeneous cohort in which all of the patients underwent total thyroidectomy, and had pathological TNM stage pT1 (≤1 cm) and N1 or NX, pT1 (>1–2cm) and any N, or pT2, N0 without thyroid capsule extension/distant metastases.
[17]
[Level of evidence: 3iA]

Thyroid ablation rates were equivalent between high- and low-dose 131I at 6 to 10 months after administration of 131I.

Complete thyroid ablation rate was 92%.

Patients undergoing thyroid hormone withdrawal had more symptoms of hypothyroidism associated with deterioration in quality of life compared with the rhTSH group.

Neither study assessed the effect of low-dose RAI on long-term recurrences or survival. The studies also did not address whether RAI could be safely omitted in specific low-risk groups.

Thyroid-suppression therapy

After thyroid surgery, all patients, except those undergoing lobectomy, will require thyroid hormone replacement therapy. For patients who have undergone thyroidectomy, supratherapeutic doses of thyroid hormone are routinely administered to suppress TSH levels. The degree of TSH suppression recommended depends on the risk of recurrence and the comorbidities of the patient. Studies have suggested that TSH suppression improves progression-free survival (PFS), but there is no definitive evidence that it improves OS.
[18]
[19]

External-beam radiation therapy (EBRT)

EBRT is typically reserved for palliative treatment of unresectable or metastatic papillary or follicular thyroid cancer. In some cases, it may be appropriate to treat with EBRT in the adjuvant setting if there is confirmed or suspected microscopic residual disease that is confirmed or suspected to be refractory to RAI. There are no randomized trials to guide the selection of patients who might benefit from treatment with EBRT. The decision to use EBRT is based on retrospective data and clinical judgment.
[20]

Metastatic papillary and follicular thyroid cancer

Total thyroidectomy is still recommended as the initial treatment for metastatic papillary or follicular thyroid cancer. RAI is the second treatment and is given to ablate the remnant thyroid and treat the metastatic disease. If a thyroidectomy is not done, then RAI is not a treatment option for the patient. The most common sites of distant metastases are the lungs and bones. Treatment of distant
metastases is usually not curative but may produce significant palliation.
Standard treatment options for iodine-sensitive and iodine-resistant metastatic papillary and follicular thyroid cancer are described below.

Standard treatment options for iodine-sensitive thyroid cancer

Standard treatment options for iodine-sensitive thyroid cancer include the following:

RAI therapy: Metastases that demonstrate uptake of this isotope may be ablated
by therapeutic doses of 131I.

Thyroid-suppression therapy.

Standard treatment options for iodine-resistant thyroid cancer

Standard treatment options for iodine-resistant thyroid cancer include the following:

OS was not significantly improved (HR, 0.80; 95% CI, 0.54–1.19, P = .14, one-sided P-value), but the median OS had not been reached at the time of primary analysis data cutoff, and crossover was allowed.

Objective response rate (all partial responses) was 12.2% in the sorafenib group compared with 0.5% in the placebo group.

Median time-to-progression was 11.1 months in the sorafenib group compared with 5.7 months in the placebo group (HR, 0.56; 95% CI, 0.43–0.72, P < .001).

Adverse events occurred in 98.6% of patients treated with sorafenib and 87.6% of patients treated with placebo. The most common adverse events in the sorafenib group were hand-foot skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Most events were grade 1 or 2. Seven squamous cell carcinomas of the skin occurred in the sorafenib group.

The primary endpoint was PFS, and secondary endpoints were OS, response rate, and safety.

The median PFS in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (HRprogression or death, 0.21; 99% CI, 0.14–0.31; P < .001). A PFS difference was observed in patients with all histologic types of thyroid cancer enrolled in this trial.

There was no significant difference in OS between the two groups (HR death, 0.73; 95% CI, 0.50–1.07; P = .10), even with the crossover design of the study.

EBRT

Patients unresponsive to 131I should also be considered candidates for
clinical trials testing new approaches to this disease.

Chemotherapy has been reported to produce
occasional complete responses of long duration.
[24]
[25]
[26]

Clinical trials evaluating new treatment approaches to this disease should be considered for patients with radioiodine refractory papillary or follicular thyroid cancer. Oral inhibitors targeting specific activating point mutations are under clinical evaluation, as are new immunotherapy approaches.
[27]
[28]
[29]
[Level of evidence: 2Dii]

Recurrent papillary and follicular thyroid cancer

Approximately 10% to 30% of
patients thought to be disease free after initial treatment will develop
recurrence and/or metastases. Of these patients, approximately 80% develop recurrence
with disease in the neck alone, and 20% develop recurrence with distant metastases. The most
common site of distant metastasis is the lung. In a single series of 289
patients who developed recurrences after initial surgery, 16% died of cancer at
a median time of 5 years after recurrence.
[5]

The prognosis for patients
with clinically detectable recurrences is generally poor, regardless of cell
type.
[30]
Patients who recur with local or regional tumor
detected only by 131I scan have a better prognosis.
[31]

The selection of
further treatment depends on many factors, including the following:

Surgery with or without postoperative RAI therapy

Surgery with or without 131I ablation can be useful in
controlling local recurrences, regional node metastases, or occasionally,
metastases at other localized sites.
[33]
Approximately 50% of the patients
who undergo surgery for recurrent tumors can be rendered free of disease with a second
operation.
[30]
Local and regional recurrences detected by 131I scan and not
clinically apparent can be treated with 131I ablation and have an excellent
prognosis.
[34]

Up to 25% of recurrences and metastases from well-differentiated thyroid cancer
may not show 131I uptake. For these patients, other standard imaging techniques such as ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography scans may detect recurrent or metastatic disease.

Patients unresponsive to 131I should also be considered candidates for clinical trials testing new approaches to treating this disease.

Targeted therapy

Sorafenib

Sorafenib is an orally active, multityrosine kinase inhibitor. It has been approved by the U.S. Food and Drug Administration as a treatment option when recurrent disease does not
concentrate 131I or disease recurs after 131I ablation.

The median PFS in the sorafenib group was 10.8 months versus 5.8 months in the placebo group (HR, 0.59; 95% CI, 0.45–0.76; P < .001).

OS was not significantly improved (HR, 0.80; 95% CI, 0.54–1.19; P = .14, one-sided P-value), but the median OS had not been reached at the time of primary analysis data cutoff, and crossover was allowed.

Objective response rates (all partial responses) were 12.2% in the sorafenib group compared with 0.5% in the placebo group.

Median time-to-progression was 11.1 months in the sorafenib group compared with 5.7 months in the placebo group (HR, 0.56; 95% CI, 0.43–0.72; P < .001).

Adverse events occurred in 98.6% of patients treated with sorafenib and 87.6% of patients treated with placebo. The most common adverse events in the sorafenib group were hand-foot skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Most events were grade 1 or 2. Seven squamous cell carcinomas of the skin occurred in the sorafenib group.

The primary endpoint was PFS, and secondary endpoints were OS, response rate, and safety.

The median PFS in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (HRprogression or death, 0.21; 99% CI, 0.14–0.31; P < .001). A PFS difference was observed in patients with all histologic types of thyroid cancer enrolled in this trial.

There was no significant difference in OS between the two groups (HRdeath, 0.73; 95% CI, 0.50–1.07; P = .10), even with the crossover design of the study.

Objective response rate was 64.8% in the lenvatinib group versus 1.5% in the placebo group (OR, 28.87; 95% CI, 12.46–66.86; P < .001).

Treatment-related adverse events (all grades) occurred in 97.3% of patients in the lenvatinib group and 59.5% of patients in the placebo group.

Grade 3 or higher adverse events were observed in 75.9% of patients receiving lenvatinib and 9.9% of patients receiving placebo.

Clinical trials evaluating new treatment approaches to this disease should be considered for patients with recurrent papillary or follicular thyroid cancer. Oral inhibitors targeting specific activating point mutations are under clinical evaluation, as are new immunotherapy approaches.
[27]
[28]
[29]
[Level of evidence: 2Dii]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Medullary Thyroid Cancer (MTC)

Sporadic and Hereditary MTC

MTC occurs in two forms,
sporadic and hereditary. In the sporadic form, the tumor is usually unilateral.
In the hereditary form, the tumor is almost always bilateral. In addition, the
hereditary form may be associated with benign or malignant tumors of other
endocrine organs, commonly referred to as the multiple endocrine neoplasia
(MEN) syndromes types 2A and 2B (MEN2A or MEN2B).
These syndromes are associated with pheochromocytoma of the adrenal
gland and parathyroid hyperplasia.

Approximately 25% of reported cases of MTC are hereditary.
Hereditary MTC syndromes include MEN2A, which is
the most common, MEN2B, and hereditary non-MEN syndromes. (Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.) Any patient with an
hereditary variant is screened for other associated endocrine tumors,
particularly parathyroid hyperplasia and pheochromocytoma. Medullary carcinoma usually secretes
calcitonin, a hormonal marker for the tumor, and may be detectable in blood
even when the tumor is clinically occult. Determining the level of calcitonin
is useful for diagnostic purposes and for following the results of treatment.

Patients with MTC (whether hereditary or sporadic) are
tested for RET mutations, and if the mutations are positive, family members will
also be tested. Family members may be screened for calcitonin elevation and for the RET
proto-oncogene mutation to identify other individuals at risk for developing
hereditary MTC. Because a modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the RET mutation is
the optimal approach. Family members who are gene carriers may choose to undergo
prophylactic thyroidectomy at an early age.
[1]
[2]

Clinical Features and Prognosis

MTC comprises 3% to 4% of all thyroid cancers.
These tumors usually present as a hard mass in the neck or thyroid, often associated
with lymphadenopathy.
[3]
MTC can also be diagnosed by fine-needle aspiration biopsy. Cytology
typically reveals hypercellular tumors with spindle-shaped cells and poor
adhesion.
[4]
Metastases to regional lymph nodes
are found in about 50% of the cases.

The overall survival rates of patients with MTC is 86% at 5 years and 65% at 10 years.

Stage Information for MTC

Several staging systems have been employed to correlate extent of disease with
long-term survival in MTC. The clinical staging system of
the American Joint Committee on Cancer correlates survival to size of the primary tumor (T), presence or absence
of lymph node involvement (N), and presence or absence of distant metastasis (M).
Patients with the best prognosis are those who are diagnosed with the hereditary form of MTC after a positive screening for a RET mutation.
[8]

T4b = Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels.

NX = Regional lymph nodes cannot be assessed.

N0 = No evidence of locoregional lymph node metastasis.

–N0a = One or more cytologically or histologically confirmed benign lymph nodes.

T4b = Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels.

NX = Regional lymph nodes cannot be assessed.

N0 = No evidence of locoregional lymph node metastasis.

–N0a = One or more cytologically or histologically confirmed benign lymph nodes.

Standard Treatment Options for MTC

Localized disease

Radioactive iodine has no place in the treatment of patients with MTC.

Total thyroidectomy

Patients with MTC are treated with a total
thyroidectomy unless there is evidence of distant metastasis. In patients
with clinically palpable MTC, the incidence of
microscopically positive nodes is more than 75%. Routine central and bilateral
modified neck dissections are generally done.
[9]
When cancer is confined to
the thyroid gland, the prognosis is excellent.

EBRT

EBRT has been used for palliation of locally recurrent
tumors without evidence that it provides any survival advantage.
[10]

Locally advanced and metastatic disease

Standard treatment options for locally advanced and metastatic MTC include the following:

Vandetanib has been evaluated in a placebo-controlled, prospective trial (NCT00410761) in 331 patients with locally advanced and metastatic disease with a 2:1 ratio in assignment to the study drug.
[11]
[Level of evidence: 1iiDiii]

Overall survival (OS) was not different at 24 months. Longer follow-up will be required because all but 47 patients were alive at the time of analysis, and there was a crossover to the study drug on progression from placebo, making analysis of OS problematic.

Vandetanib has significant side effects, including diarrhea, rash, hypertension, and QT prolongation. Quality of life was not formally assessed in this trial.

Cabozantinib

Cabozantinib has been evaluated in a randomized, double-blind, placebo-controlled, phase III trial (EXAM [NCT00704730]) in 330 patients with metastatic MTC and radiographic progression of disease. Patient were randomly assigned in a 2:1 ratio to receive cabozantinib (140 mg per day) or placebo. Patients receiving placebo were not permitted to cross
over to cabozantinib.
[12]
[Level of evidence: 1iDiii]

The primary endpoint of the study was PFS, and additional outcome measures were response rate, OS, and safety.

Estimated median PFS was 11.2 months in the cabozantinib group and 4.0 months in the placebo group (HR, 0.28; 95% CI, 0.19‒0.40; P < .001). A difference in PFS was observed across all subgroups and was independent of previous tyrosine kinase inhibitor treatment and RET mutation status.

During a planned interim analysis of OS, no statistically significant difference was observed between the two groups (HR, 0.98; 95% CI, 0.63‒1.52).

Objective response rate was 28% in the cabozantinib group (all partial responses) and 0% in the placebo group (P < .001). The median estimated duration of response was 14.6 months (95% CI, 11.1‒17.5 months). Responses were observed regardless of RET mutation status.

Grade 3 or 4 adverse events were reported in 69% of patients in the cabozantinib group and 33% of patients in the placebo group.

Adverse events resulted in treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.

Palliative chemotherapy

Palliative chemotherapy has been reported to produce occasional responses in
patients with metastatic disease.
[13]
[14]
[15]
[16]
No single drug regimen can be
considered standard. Some patients with distant metastases will experience
prolonged survival and can be managed expectantly until they become
symptomatic.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Anaplastic Thyroid Cancer

Clinical Features and Prognosis

Undifferentiated (anaplastic) carcinoma is a highly malignant cancer of
the thyroid. It grows rapidly and extends to structures beyond the thyroid. It typically presents as a hard, ill-defined mass, often with
extension into the structures surrounding the thyroid. Anaplastic
thyroid cancer must be carefully distinguished from lymphoma, which can have a similar presentation. This tumor
usually occurs in an older age group and is characterized by extensive local
invasion and rapid progression.
[1]

Five-year survival with this tumor is poor.
Death is usually from uncontrolled local cancer in the neck, usually within
months of diagnosis.

Stage Information for Anaplastic Thyroid Cancer

All patients with anaplastic thyroid cancer are considered to have stage IV disease.

Standard Treatment Options for Anaplastic Thyroid Cancer

Surgery

If the disease is confined to the local area, which is rare, total thyroidectomy is warranted to
reduce symptoms caused by the tumor mass.
[2]
[3]
Tracheostomy is frequently necessary.

EBRT

EBRT may be used in patients who are not surgical candidates or whose tumor cannot be surgically
excised.

Chemotherapy

Anaplastic thyroid cancer is not responsive to iodine 131I therapy.
Treatment with individual anticancer drugs has been reported to produce partial
remissions in some patients. Approximately 30% of patients achieve a partial
remission with doxorubicin.
[4]
The combination of doxorubicin plus cisplatin
appears to be more active than doxorubicin alone and has been reported to
produce more complete responses.
[5]

The combination of chemotherapy plus radiation therapy in patients after complete
resection may provide prolonged survival but has not been compared with any one
modality alone.
[6]
[7]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult thyroid cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Thyroid Cancer Treatment (Adult) are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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